Synthesis of steroids



United States Patent 3,288,811 SYNTHESIS OF STEROIDS Gerald W. Krakower,Elizabeth, and Hilda Van Dine, Princeton, N.J., assignors to E. R.Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware NoDrawing. Filed Feb. 10, 1966, Ser. No. 526,356 4 Claims. (Cl. 260-3452)This application is a con-tinuation-in-part of prior filed application,Serial No. 457,499, filed May 20, 1965.

This invention relates to and has as its object the provision of newphysiologically active steroids, novel methods for their production andnew intermediates useful in said preparation. More particularly, thisinvention relates to the preparation of compounds of the formula:

R!!! CH CH; wherein R is hydrogen and R" is hydroxy or acyloxy; andtogether R" and R' is 0x0 (0 The preferred acyl and acyloxy radicals arethose of hydrocarbon carboxylic acids of less than twelve carbon atoms,as exemplified by the lower alkanoic acids (e.g., acetic, propionic,butyric and tert-pentanoic acid), the lower alkenoic acids, themonocyclic aryl carboxylic acids (e.g., benzoic and toluic acid), themonocyclic aryl lower alkanoic acids (e.g., phenacetic andB-phenylpropionic acid), the cycloalkane carboxylic acids and thecycloalkene carboxylic acids.

The final products of this invention wherein R" and R' together is 0x0in the 17-position are physiologically active steroids which possessuterotriphic activity and may be used in the treatment of suchconditions as menstrual disorders'and compounds of this inventionwherein R" is hydroxy or acyloxy and R is hydrogen are physiologicallyactive steroids which possess anti-androgenic activity, (i.e., they canbe utilized in the treatment of such conditions as hyperandrogenicacne). These compounds are formulated for such administration in themanner and/ or dosage as determined by the respective compound involvedand the requirements of the patient.

The final compounds of this invention may be prepared according to theprocesses of this invention which may be represented by the followingequations wherein R and R'" are as hereinbefore defined:

In the first step of the novel process of this invention, the star-tingmaterals (Compounds A) are reduced as by treatment with a reducingagent, for example, an alkali metal borohydride, such as sodiumborohydride, to yield the l1-hydroxy-l6 unsubstituted derivativesthereof, The starting materials (Compounds A) which may be employed inthe practice of this invention are those which maybe prepared byreducing a compound having the formula with acid, acid anhydride, andtoluene sulphonic acid.

The 3-hydroxy compounds may be mono-acylated as by treatment with anacylating agent, for example, acid anhydride or acyl halide in thepresence of an organic base, such as collidine or pyridine, to yield the3-acylated derivatives. The processes for preparing the startingmaterials of the instant invention are more fully set forth in a priorapplication, Serial No. 419,231, filed December 17, 1964, in the namesof Gerald W. Krakower and Hilda Anne Schwartz.

The 3,11-dihydroxy compounds are first mono-acylated as by treatmentwith an acylating agent, for example, acid anhydride or acyl halide, inthe presence of an organic base, such as collidine or pyridine, to yieldthe 3-acylatedll-hydnoxy derivatives.

The 3-acylated-l1-hydroxy derivatives may then be dehydrated as bytreatment with a dehydrating agent, for example, an inorganic acidhalide such as thinoyl chloride in an organic base, such as collidine orpyridine to yield the 3-acyloxy-9,ll-dehydro novel final products of thein stant invention. These final products may be also utilized asintermediates in the preparation of 3;8,l7aot-dihydroxy and3p-acyloxy-17au-hydroxy derivatives of this invention. The3-a-cyloxy-9,11-dehydro compound may be reduced as by treatment with areducing agent, for example, an alkali metal borohydride, such as sodiumborohydride, to yield these derivtive, i.e., 3B,l7aa-dihydroxy and3aacyloxy-l7aa-hy-droxy steroids of the invention.

In addition, the 3-acyloxy-9-11-dehydro final products may be furthertreated to yield the .other novel final prod nets of this invention. The3-acyloxy-9,ll-dehydro compounds may be hydr-olized as by treatment withan alcoholic alkali metal hydroxide, for example, ethanolic po- 0tassium hydroxide to yield the 3-hydroxy-9,11-.dehydro novel finalproducts of this invention.

The 3-hydroxy-9,1l-dehydro and 3,17-dihydroxy final products may then beoxidized as by treatment with an oxidizing agent, such as chromic acidto yield the 3,17- diketo-9,11-dehydro final products of this invention.

The invention may be further illustrated by the following examples:

A suspension of 250 mg. of 301,16fi-diacetoxy-4a,8,14-trimethyl-17-oxa-D-homo-18-nor-5a,8a,9,813a,14p and- -stane-11,17a-dionein 25 ml. of absolute ethanol is treated with mg. of sodium borohydride,and stirred at room temperature. After ten minutes the substratedissolves and after seventy-five minutes the reaction mixure is acidiafied with glacial acetic acid. The solvent is evaporated and the'residueis taken up in ethyl acetate. After Washing with saturated salt solutiondrying and evaporation of the solvent, 210 mg. of crystalline materialis obtained. Two recrystallizations from methanol give 84 mg. ofanalytically pure 3ot-acetoxy-l1a-hydroxy-4a8,14-trimethyl- 17oxa-D-homo-18-nor-5a,8a,9p3,13a,14B-androstane- 17a-one, M.P. 209212 C.,[ab-" 55.5.

Analysis.-Calcd for C H O C,70.37; H, 9.24. Found: C, 70.00; H, 9.66.

Example 2.3a-acet0xy-4 a,8,1 4 trim ethyl 1 7 oxa-D- homo-18-i10r-5cc,8oc,9,8,1 301,1 4B-andr0stane-1 1 ,17a-dine A solution of 48mg. of 3a-acetoxy-11a-hydroxy 4ot,8,14-trimethyl-l7-oxa DhOInO-l8-I1OI'5oc,8a,9/3,13oz, 14fl-androstane-17a-one in 2 ml. ofacetone is treated With an excess of chromic acid-sulfuric acid reagent.After five minutes at room temperature, the excess chromic acid isreduced with methanol and the solution diluted with Water. The solventis evaporated and the aqueous suspension is extracted with methylenechloride. The methylene chloride solution is washed with saturated saltsolution, dried and evaporated to give 34 mg. of material.Recrystallization from methanol gives 20 mg. of3a-acetoxy-4a,8,14trimethyl-17-oxa-D hOInO-l8-I1OI'5oc,8oc,9fi,13a,14fl-androstane-1l,17a-dione, M.P. 214215 C., 9.4.

, Analysis.Calcd for C H O C, 70.74; H, 8.78. Found: C, 70.78; H, 8.74.

A suspension of 400 mg. of 16{3-acetoxy-4ot,8,14-trimethyl-17-oxa-Dhomo-18-nor-5a,8a,9B,13a,14fl-androstane-3,l1,17a-trione in 40 ml. ofabsolute ethanol is treated with 300 mg. of sodium borohydride andstirred at room temperature for three hours. The reaction is then workedup as described in Example 1 to give 373 mg. of crude3fi,l1a-dihydroxy-4a,8,14 trimethyl l7-oxa-D homo-lS-nor5ot,8a,918,13a,14fi androstane 17a one. Recrystallization from methanolgives 79 mg, 279-284 C. The analytical sample has M.P. 283284 C.

Analysis.Calcd for C I-1 0 C, 71.96; H, 9.78. Found: C, 72.00; H, 9.60.

3 8,11a-dihydroxy-4a,8,14-trimethyl-17 oxa-D homo-18-nor-5a,8tx,9,8,13a,14,8-androstane-17a-one is dissolved in a mixtureof pyridine-acetic anhydride and left overnight at room temperature.After addition of water the mixture is evaporated and the residuerecrystallized from methanol to give3B-acetoxy-11ot-hydroxy-4a,8,14-trimethyl-17-oxa D-homo-lS-nor5a,8ot913,13oc,14,6-androstane-17a-one, M.P. 197-198 C., [041 13.5(chloroform).

Analysis.Calcd for C H O C, 70.37; H, 9.24. Found: C, 70.51; H, 9.18.

Similarly, following the procedure of Example 4, but susbstitutingequivalent amounts of other acylating agents, for example, propionylanhydride or benzoyl chloride for acetic anhydride, there is obtainedthe respective 3-propionate and 3-benzoate derivatives.

Example 5.3/3-acetoxy-4a,8,14 trime2hyl-I7 oxa-D- homo-1 8-n0r-5ot,8-a,1 3 01,1 4 ,8-andr0st-9( 1 .l )-ene-1 7a-one A solution of 50 mg.of thionyl chloride in 0.5 ml. of pyridine is added to 50 mg. of 38-acetoxy-llu-hydroxy- 4a,8,l4-trimethyl-17 oxa-D-homo-lS-nor5a,8oc,9,8,13w 14,8-androstane-17a-one in 1 ml. of pyridine cooled to-20 C. The reaction mixture is kept at 0 C. for thirty minutes and thenquenched with Water and extracted with ethyl acetate. The ethyl acetatesolution is Washed with 5% hydrochloric acid and saturated sodiumchloride solution, dried and evaporated to give 43 mg. of crudematerial. Recrystallization from methanol gives 22 mg. of3fi-acetoxy-4a,8,14-trimethyl 17-oxa-D-homo-l8-nor-5a,8a,13a,14,B-androst-9(11)-ene-l7a-one, M.P. 255 -25 6 C., [al 30.2(chloroform).

Analysis.Calcd for C H O Found: C, 73.64; H, 9.12.

A solution of 81 mg. of 3li-acetoxy-4a,8,l4-trimethyll7 oxa Dhomo-l8-nor-5a,8 x,13a,14fl-androst-9(l1)- ene-17a-one, in 25 ml. of 5%ethanolic potassium hydroxide is left overnight at room temperature. Thesolution is then acidified with 20% sulfuric acid, diluted with waterand the solvent evaporated. The aqueous suspension is extracted withethyl acetate and Washed with saturated salt solution, dried andevaporated to give crude SB-hydroxy 4 x,8,14trimethyl-l7-oxa-D-homo-18-nor-5a,8a,13m,14,8-androst-9(11)-ene-l7a-one.

Oxidation of the material of Example 6 with chromic acid-sulfuric acidas described in Example 2 gives crude 4oc,8,14trimethyl-l7-oxa-D-homo-18-nor-5u,8a,130:,14/3-androst-9(11)-ene-3,17a-dione.

To a solution of 500 mg. of 3fi-acetoxy-4a,8,l4-trimethyl 17oxa-D-homo-18-nor-5a,8u,13a,l4}3-androst- 9(l1)-ene-l7a-one in 20 ml. ofdioxone is added 500 mg. of sodium borohydride in 20 ml. of 1:1dioxane-water. The mixture is stirred at room temperature for seventeenhours and then glacial acetic acid is added to decompose excessborohydride. The solution is acidified to pH 2 with 5% hydrochloric acidand the solvent evaporated. The residue is only partially soluble inethyl acetate. The insoluble portion, 166 mg., on recrystallization frommethanol, affords 3,8,17aa dihydroxy 4u,8,l4-trimethyl- The crudemixture from the sodium borohydride reduction of 100 mg. of3fi-acetoxy-4a,8,14-trimethyl-l7-oxa- D homol8-nor-5a,8a,l3a,14(3-androst-9(1l)-ene-l7a one is dissolved in amixture of 2 ml. of pyridine and 1 ml. acetic anhydride and leftovernight at room temperature. Water is added to the reaction mixtureand it is then evaporated in vacuo. Recrystallization of the residuefrom methanol gives 73 mg; of 35,17aa-diacetoxy-4ot,8,l4- trimethyl17-oxa-D-homo-18-nor 5a,8a,13a,14fi-androst- 9(11)-ene, M.P. -96 C. Theanalytical sample has M.P. 9899 C. [a] -1O (methanol).

Analysi.r.Calcd for 0 .3 0 0, 71.74; 9.15.-

Found: C, 71.55; H, 9.24.

While there have been described various embodiments of the invention,the compositions and methods described are not intended to be understoodas limiting the scope of the invention, as it is realized that changestherein are possible and it is further intended that each elementrecited in any of the following claims is to be understood as referringto all equivalent elements for accomplishing substantially the sameresults in substantially the same or equivalent manner, it covering theinvention broadly in whatever form its principle may be utilized.

What is claimed is:

1. A compound of the formula 6 wherein R' is hydrogen; R" is selectedfrom the group consisting of hydroxy and acyloxy, wherein the acylradical is of a hydrocarbon carboxylic acid of less than twelve carbonatoms.

2. A compound in accordance with claim 1 having the name3B,17aa-dihydr0Xy-4m,8,14-trimethyl-17-oxa-D-hOmO-18-IlOr-50t,8a,13d,14B-al1dI'OSt-9(11)-Il6.

3. A compound in accordance with claim 1 having the name3B-acetoxy-17aa-hydroxy-4u,8,14-trimethyl-17-oxa-D-homo-18-nor-5a,8a,13a,14,6-androst-9( l 1 )-ene.

4. A compound in accordance with claim 1 having the name 35,17aadiacetoxy 40:,8,14-trimethyl-17-oxa-D-hOmO-l8-I10f-5a,8oc,l3oc,14[3andr0St-9(l1)-I16.

No references cited.

WALTER A. MODANCE, Primary Examiner.

JAMES A. PATTEN, Assistant Examiner.

1. A COMPOUND OF THE FORMULA